Parishin degrades CXCL2 via ubiquitination to limit myeloid-derived suppressor cells and potentiate antitumor immunity after incomplete radiofrequency ablation in hepatocellular carcinoma.
TL;DR
This study elucidates the adverse role of the CXCL2/MDSC axis in the prognosis of post-iRFA HCC and reveals a novel "Parishin-CXCL2 ubiquitination" mechanism.
Abstract
Radiofrequency ablation (RFA) is a standard curative therapy for early-stage hepatocellular carcinoma (HCC). However, some patients experience incomplete RFA (iRFA), and the chemokines and cytokines released subsequent to iRFA can promote tumor progression. Based on transcriptomic data from HCC patient-derived organoids (PDOs) (source: 2024 Cancer Cell 38,593,780) and in vivo models before and after iRFA, this study identified CXCL2 as a key differentially expressed gene. This chemokine shapes an immunosuppressive microenvironment by recruiting immunosuppressive myeloid cells. Survival analysis of HCC patients who underwent ablation for postoperative recurrence revealed that CXCL2 expression is significantly associated with overall survival. Through the screening of 4566 natural products, we identified Parishin as a compound that specifically targets CXCL2. Mechanistically, Parishin does not act via receptor antagonism; rather, it directly binds to the Q24, S25, and S27 residues of CXCL2, promoting it subiquitination at the K88 site and subsequent proteasomal degradation. In cellular experiments, Parishin (80 μM) concentration-dependently reduced CXCL2 protein levels in iRFA-treated Huh7 and H22 cells without affecting its transcription. In vivo animal studies demonstrated that intraperitoneal administration of Parishin (50 mg/kg, every other day) significantly suppressed tumor growth in mice bearing iRFA-treated tumors. Single-cell RNA sequencing (scRNA-seq), immunofluorescence, and flow cytometry further confirmed that Parishin reduced the infiltration of myeloid-derived suppressor cells (MDSCs), increased the proportion of CD8+ T cells, and reversed the immunosuppressive microenvironment. This study elucidates the adverse role of the CXCL2/MDSC axis in the prognosis of post-iRFA HCC and reveals a novel "Parishin-CXCL2 ubiquitination" mechanism. These findings offer a potential therapeutic strategy for iRFA-related recurrence and hold significant translational value for optimizing clinical RFA protocols.